Clomipramine is a kind of a selective serotonin reuptake inhibitor (SSRI).
The clomipramine is a representative tricyclic antidepressant (TCA), and used as a therapeutic agent for premature ejaculation (Product Name: Anafranil). Diagnostic criteria of the premature ejaculation is DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision), and according to this definition, the premature ejaculation refers to a case of persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration.
The clomipramine can be administered into blood, but when considering the case of using a therapeutic agent for premature ejaculation and/or an antidepressant, and convenience of drug intake and portability due to characteristics of disease, oral formulation is preferred. Further, tablets containing clomipramine hydrochloride of 10 mg, 15 mg, 25 mg, 50 mg or 75 mg are commercially available, and it is reported that low dose has very little therapeutic effect like a placebo. For example, because it is recommended to administer the clomipramine hydrochloride of 250 mg per day for effective treatment for obsession, unit dose is large. However, because the clomipramine hydrochloride has a unique bitter taste together with a spicy taste, an burning taste and the like, there are problems of giving an unpleasant feeling when administered orally, causing local paralysis in the mouth in a severe case and the like. Thus, it is difficult to manufacture it in the formulation for oral administration, in particular, orally dispersible formulation whose taste is directly felt when orally administered, for example, orally disintegrating film, orally disintegrating table, suspension, dispersible tablet, fast-acting disintegrating tablet, orally disintegrating capsule, orally disintegrating granule, orally disintegrating troche, sublingual tablet, powder and/or chewable tablet.
More specifically, the reasons why the formulation for oral administration comprising the clomipramine hydrochloride as an active ingredient is limited are as follows.
There are many difficulties to manufacture the clomipramine hydrochloride in the formulation for oral administration because it has strong spicy taste and burning taste with a unique bitter taste and also has a symptom of tongue paralysis and the like.
Accordingly, first, in order to make taste masking (TM) of a unique taste due to the clomipramine hydrochloride and prediction of absorption pattern (for example, Cmax, Tmax) possible, a large amount of a taste masking agent and a large coating amount should be needed, and as a result, there is no choice but to increase a loading weight in a formulation
Second, or, in order to load a large amount of the TM agent in a formulation having limited size, the amount of the clomipramine hydrochloride and other additives to be added is limited. Thus, in this case, it is difficult to manufacture a formulation having satisfactory activity, physical properties and a handling property.
Third, in order to manufacture the clomipramine hydrochloride in the film formulation, it is necessary to use a polymer in a certain amount or more for maintaining film shape. However, in order to load a large amount of a taste masking agent and a large coating amount in a film having limited size, the amount of the polymer should be highly decreased. If the amount of the polymer is not enough, it is difficult to have proper physical properties to handle the formed film (for example, flexibility, tensile force).
Finally, the largest problem is that it is difficult to completely mask all unpleasant tastes because the burning taste can't be masked even if the unique bitter taste and spicy taste can be masked by using a taste masking TM agent commonly used for taste masking of a pharmaceutical preparation.